In the aging US population, the rate of hip and knee replacements doubled between 2000 and 2010. Although an individual’s risk for infection remains low, the high frequency of replacements is increasing the number of infections and the burden of infectious disease. Infections routinely are recalcitrant to antibiotic therapies regardless of whether the infecting bacteria are susceptible or resistant to current standard of care, including antibiotics. Following an initial acute phase, infection commonly evolves into a chronic inflammatory osteomyelitis as episodes of relapsing infection develop within surrounding bone and joint tissue. The source of relapsing infection remains incompletely understood. Clinical and experimental evidence suggests that bacteria invade host cells surrounding the implanted prosthetic device and evade antibiotic therapies to reemerge as a source of relapsing infection. The personal and economic burden of chronic, relapsing infections underscores the need for alternative and adjunctive therapeutic approaches.

Our research groups are focused on developing therapies that limit host cell invasion to break the cycle of relapsing infection. We have discovered a host protein used for invasion by Staphylococcus aureus, the infecting agent commonly identified in prosthetic joint infections. We have characterized pharmacology of ML141, a small molecule inhibitor with specificity for the host protein. We are examining the hypothesis that by targeting this host protein, ML141 would be efficacious in limiting relapsing S. aureus infection.

Panel A. 1 In the absence of ML141, S. aureus bound to host fibronectin interacts with the host cell integrin 51, stimulating GTP-loading and activation of CDC42. 2 GTP-loading of CDC42 increases affinity for the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K). CDC42, coupled to PI3K through the p85 subunit, positions the catalytic domain p110 in proximity with phosphoinositide4,5-bisphosphate (PI4,5). 3 The product of the phosphorylation of PI4,5 by p110 is PI 3,4,5-trisphosphate (PIP3), capable of promoting endocytosis of the bacterium/fibronectin/integrin complex4.

Panel B. In response to the inhibition of GTP-loading of CDC42 by ML 141, 1CDC42 remains uncoupled from p85. Consequently, p110 remains within the cytosol. By sequestering p110 within the cytosol, membrane-bound PI4,5 is not accessible, diminishing PIP3 production. Diminished generation of PIP32 limitsendocytic uptake of the bacterium/fibronectin/integrin complex, protecting the host cell from bacterial invasion.